Production of arecoline



Patented Sept. 25, 1951 PRODUCTION or ARECOLINE Joseph Levy, Union, N.J., iassignor to Nopco Chemical Company, Harrison, 'N. J a corporationof NewJersey 'No Drawing. Application September 23, 1949,

Serial Not 117,513

9 Claims. (Cl. 260295.5)

This invention relates to arecoline and to an improved process forpreparing it.

Arecoline is the methyl ester of arecaidine, i. c. it is the methylester of N-methyI-A -tetrahydropyridine-3-carboxy1ic acid. Arecoline hasimportant pharmaceutical uses, the most important of which is its use byveterinarians as an anthelmintic for which purpose it is usuallyemployed in the form of its hydrobromide salt. In the past this compoundhas been obtained almost entirely from betel nuts inasmuch as nopractical commercial methods for producing it synthetically have beenavailable. Numerous proposals for synthetically producing this compoundhave been made but in practically all cases such methods have been quitecomplicated, involving long and" drawn out procedures and resulting invery poor yields of the compound.

In the co-pending U. S. patent application of Lawrence H. Knox, SerialNo. 724,243, filed January 24, 1947, now U. S. Patent No. 2,506,458patented May 2, 1950, a new and very highly improved process for theproduction of arecoline is disclosed and claimed. v In one of the stepsof this novel process, the methyl ester of N-methyl-4-hydroxypiperidine-3-carboxylic acid is dehydrated by removal of thehydroxy group from the 4 position and the hydrogen atom from the 3position to form a double bond between the 3 carbon atom and the 4carbon atom, thus giving arecoline. This dehydration step of the processof Patent No. 2,506,458 is carried out by admixing the hydrochloridesalt of the 4-hydroxypiperidine compound with either thionyl chloride orphosphorus oxychloride. The outstanding aspect of said invention is thatthe dehydration of the hydroxypiperidine compound.

is accomplished without hydrolysis of the ester group on the 3 position.In the prior art when dehydration of such 4-hydroxypiperidine compoundswas accomplished with mixtures of acetic acid and hydrochloric acid orhydrochloric acid and potassium iodide the ester group wassimultaneously hydrolyzed to the free acid. Furthermore, the previousmethods for dehydrating the hydroxypiperidine compounds required periodsof time of'from to hours to accomplish the dehydration step. The processof Patent No. 2,506,458, on the other hand, requires only a relativelyshort time for the dehydration inasmuch as the hydroxypiperidinecompound is merely admixed with either thionyl chloride or phosphorusoXychloride by the dropwise addition of the dehydrating agent to thehydroxy' piperidine. The dehydration is completed in ahydroxypiperidine.

hydrobromide salts;

short time after all of the required amount of dehydrating agent hasbeen added to the Another disadvantage of the prior art methods employedprevious to the discovery of the aforesaid dehydration process was thatthe prior art methods necessitated a subsequent esterification of thefree acid, 1. e. arecaidine, with methyl alcoholjn order to produce thedesired arecoline. This esterification step required a period ofapproximately 16 hours to accomplish. Thus these previous methodsrequired a total reaction time of from about 35 to 40 hours to producethe desired arecoline from the methyl ester ofN-methyl-4-hydroxypiperidine-3-carboxylic acid. The process of PatentNo. 2,506,458 is a marked improvement over the prior art methodsinasmuch as it accomplishes in a single step and in a very short time aresult for which the prior art processes require two stepsand from 35 to40 hours. Although the dehydration process of Patent No. 2,506,458 is anoutstanding improvement over the prior art methods, there are a fewfeatures regarding this process which could be substantially improved.In addition to producing the desired compound having the double bondbetween the 3 carbon atom and the 4 carbon atom, i. e. arecoline, thisdehydration process also results in the production of a substantialamount of an undesired isomer having the double bond between the 4carbon atom and the 5 carbon atom. The two isomers can be separated fromeach other with a fair degree of success by crystallization of theirhowever, it is somewhat difficult even by this means to producearecoline hydrobromide having a melting point greater than C. TheNational Formulary specifications state that arecoline hydrobromideshould have a'melting point between 170 C. and C.

It is seen, therefore, that the purity of the arecoline produced by thedehydration process of Patent No. 2,506,458 is not as high as desired.Furthermore, that dehydration process results in a yield of arecoline inmost cases of only about 45% based on the amount of 4-hydroxypiperidinecompound treated. A further disadvantage of the process of Patent No.2,506,458 is that it is rather difiicult to isolate all of the arecolinefrom the dehydration reaction mixture as the free base without efieotingsaponification of the ester group and thus causing the loss of asubstantial percentage of the arecoline. After that dehydration step iscompleted, alkali is added to the reaction mixture to convert thehydrochloride salt of the arecoline formed in the'process to the freebase. Thereafter the free arecoline is extracted from the reactionmixture with a solvent such as chloroform or toluene. It has been found,however, that while a strong alkali is required to completely liberatethe arecoline base from its hydrochloride salt, the use of such strongalkali causes a substantial percentage of the ester groups at the 3position to be saponified during the isolation process thus reducing theyield of the arecoline. Another disadvantage of this process is theformation of S02 and l-ICl fumes both of which are noxious and are quitecorrosive and require special equipment for removal.

It is the object of this invention to provide an improved process forthe dehydration of the esters ofN-methyl-4-hydroxypiperidine-3-carboxylic acid.

A further object of the invention is to provide an improved process forthe production of arecoline.

Another object of this invention is to provide a dehydration processwhich will produceprimarily the A isomer ofl-methyl-3-carbomethoxy-tetrahydropyridine.

Other objects of the invention will in part be obvious and will in partappear hereinafter.

I have discovered that the dehydration of esters ofN-methyl-4-hydroxypiperidine-3-carboxylic acid may be very efficientlycarried out in a very short time by heating such esters with anhydrousoxalic acid. The dehydration is accomplished in a very short time withlittle or no hydrolysis of the ester group at the 3 position.Furthermore, the product which is obtained contains a very highpercentage, i. e. 90% or better,

of the desired arecoline and only a very small percentage, if any, ofthe undesired ester having the double bond in the 4,5 position. Sincethis is the case, arecoline hydrobromideof a very high state of puritymay be readily isolated from the product by crystallization of thehydrobromide salts. Furthermore, the total yield of arecoline which isobtained by this process is usually at least about 25% to 50% greaterthan the yield which can be obtained by the process of Patent No.2,506,458. Moreover, the free base is readily liberated from the oxalatesalt thereof with a weak alkali without any appreciable saponificationof the ester groups. Preferably the free base is reacted with the oxalicacid although if desired the acetate or hydrochloride salts of the basemay be reacted with the oxalic acid.

In carrying out the dehydration of the 4-hydroxypiperidine compound withthe anhydrous oxalic acid, the piperidine compound and the oxalic acidmay be heated together either in the presence of or in the absence of asuitable entraining agent. In most cases it is preferred that thedehydration be carried out in the presence of an entraining agent whichwill aid in rapidly removing the water from the reaction mixture as soonas the water is formed inasmuch as the presence of water in the reactionmixture at the elevated temperatures employed in the process has atendency to effect the hydrolysis of the ester group on the 3 position.However, very excellent yields of arecoline may be obtained merely byfusing the oxalic acid and the piperidine compound with each other andheating them together for a short time at an elevated temperature.

The temperature at which the oxalic acid and the hydroxypiperidinecompound are heated must in order to remove the water be above 100 C.,of course, if the heating is carried out at at- 4 mospheric pressure inthe absence of an entraining agent. In most cases it is preferred not togo above about 160 C. inasmuch as temperatures in excess of 160 C. oftenhave a tendency to cause decomposition of the hydroxypiperidine compoundand of the arecoline. In carrying out such heating, the heating may beconducted at atmospheric pressure and in most cases it is preferred toheat the reaction mixture at such pressure. If desired, however, thedehydration step maybe carried out under a vacuum in which case somewhatlower temperatures can be employed; however, even when a vacuum isemployed during the dehydration step it is greatly preferred to heat thereaction mixture to a temperature between about C. and about 160 C. withtemperatures of from about to about C. being the preferred range bothwhen the .heating is carried out at atmospheric pressure and when it iscarried out under vacuum and also both when an entraining agent isemployed and when an entraining agent is not employed.

In the event that an entraining agent is employed in the dehydrationstep, hydrocarbons such as naphtha, octane, nonane, decane, xylene,toluene, ethyl benzene, cumene, propyl benzene, methyl cyclohexane,etc., are employed. The naphtha which is employed should have a boilingpoint between about 100 C. and about C. These compounds are allhydrocarbon solvents and any hydrocarbon solvent, either aromatic oraliphatic, which has a boiling point between about 100 C. and about 160C. is quite suitable for use as an entraining agent in the process of myinvention. When a solvent is employed, the dehydration reaction isordinarily carried out under reflux conditions. Preferably I employxylene and carry out the dehydration step by heating the mixture ofxylene, oxalic acid and the hydroxypiperidine at the reflux temperatureof the xylene.

When a solvent is employed as an entraining agent in the dehydrationprocess, the amount of the solvent may vary considerably. The solventdoes not actually enter into the dehydration reaction but it does aid inthe very rapid removal from the reaction mixture of the water as soon asit is formed. I have found that this is an important factor since thepresence of water in the hot reaction mixture apparently tends to causea small percentage of the ester groups at the 3 position to behydrolyzed. This is evident from the fact that higher yields ofarecoline are obtained when such an entraining agent is employed duringthe dehydration reaction than when one is not employed. Ordinarilysufficient solvent is employed to give a readily stirrable mixture ofthe solvent, oxalic acid and hydroxypiperidine; however, since even avery small amount of the solvent will to some extent aid in the rapidremoval of the water, one can if desired use only very small amounts ofsolvent as an entraining agent. Likewise there is no particular upperlimit on the amount of solvent employed other than convenience andeconomy of operation.

The length of time of heating the reaction mixture will vary somewhatdepending upon the temperature at which the reaction mixture is heatedwith slightly longer times of heating being required at the lowertemperatures and shorter times of heating being utilized at the highertemperatures. The presence or absence of an entraining agent in mostcases does not seem to make any particular difference as to thearecoline to the free base.

length of time which the reactionmixture must be heated; but thepresence of such an agent does appear to increase the yield of thedesired product possibly by aidingin the more or less instantaneouselimination of water from the reaction-mixture as soon as it is formedand thus preventing anyappreciable amount of hydrolysis of the estergroups at the 3 position from occurring. When the reaction mixture isheated at a temperature of from about 130 C. to about 150 0., reactiontimes of from about 3 to about 4 hours are quite suitably employed. Whenxylene is employed as an entraining agent, the reaction mixture isheated at the reflux temperature of the xylene; and under suchconditions I have found that a reaction time of 3 hours gives veryexcellent results. However, as I, have just pointed out, the reactiontime will vary depending upon the particular reaction temperature whichis utilized.

The amount of oxalic acid which is employed in my novel process shouldbe suffi'cient, of course, to completely dehydrate the hydroxypiperidinecompound. An amount of oxalic acid slightly in excess of that requiredto convert the hydroxypiperidine compound to the oxalate salt thereof,i. e. slightly more than mole of the oxalic acid per mole of thehydroxypiperidine compound, will accomplish this result; but in order toobtain the most efiicient results, I greatly prefer to employ about 2moles of oxalic acid per mole of hydroxypiperidine and, if de- 7 sired,larger ratios of oxalic acid to the hydroxypiperidine compound may beemployed. In order to effect the desired dehydration it is necessarythat th oxalic acid which is reacted .with the hydroxypiperidinecompound be anhydrous oxalic acid. Of course, if desired, one can admixhydrated oxalic acid with the hydroxypiperidine compound and then heatthe mixture until the water of hydration is driven from the oxalic acidand thereafter carry out the dehydration. I prefer, however, to removeany water of hydration from the oxalic acid prior to admixing it withthe hydroxypiperidine compound.

Following the completion of the dehydration step, the desired arecolineis readily recovered from the reaction mixture in any convenient manner.I prefer to cool the reaction mixture to about 100 C. and then addthereto approximately one to two parts of water for each part of theoriginal mixture of oxalic acid and hydroxypiperidine compound afterwhich the entraining agent, which forms a solvent layer, is

The solvent layer is then washed with small portions of water, whichwashes are added to the aqueous solution of the arecoline. The combinedaqueous extracts are then neutralized with some weak base such aspotassium or sodium carbonate-in order to convert the oxalic acid saltof the If the dehydration reaction is carried out in the absence of anentraining agent, the reaction mixture is dissolved in water oncompletion of the dehydration reaction using the same amount of water aswhen such an agent had been employed in the process, and then the oxalicacid .salt of the arecoline is converted to the free base in the samemanner as in the aqueous mixtures obtained from the reactionscarried'out in the presence of an'entraining agent. Thefree base isrecovered from the aqueous. mixtures by ex- :traotionwith. awater-immiscible :solvent .such

7 group at that position.

as ether, benzene, toluene, isopropyl acetate, etc, and the arecoline isrecovered from the solvent merely by distilling the solvent from thesolvent solution.

The product which is isolated from the dehydration reaction mixture is amixture of arecoline, the isomerthereof having the double bond betweenthe 4 carbon atom and the 5 carbon atom and unknown by-products, withabout or more of the product being the desired arecoline. The arecolineis readily isolated in very pure form by treating the crude productwith. ethanol containingan equivalent weight of anhydrous hydrobromicacid. Arecoline hydrobromide forms very readily in such a mixture andseparates therefrom as colorless needles on cooling with thehydrobromide of the undesired isomer remaining in solution. Inpractically every case it will be found that the arecoline hydrobromideproduced in this manner will have a melting point of from l72-l74 C.This is from 2 to 4 0. higher than the melting point of the productordinarily isolated from natural sources or the melting point of theproduct obtained by theprocess of Patent No. 2,506,458. Furthermore, thearecoline hydrobromide produced by the process of my invention may berecrystallized from ethanol to give arecoline hydrobromide having amelting point of 175 C.

The description which I have given above has described the process of myinvention with reference to the dehydration of the methyl ester of Nmethyl-4-hydroxypiperidine-3-carboxyli v acid. My process, however, willgive excellent.- results in the dehydration of other esters of 4hydroxypiperidine 3 carboxylic acid compounds. It is particularly usefulfor the production of homo-arecoline from the ethyl ester of N-methyl 4hydroxypiperidine 3 carboxylic acid. Homo-arecoline differs fromarecoline only in that it has an ethyl ester group at the 3 positionwhereas arecoline has a methyl ester Homo-arecoline may readily beconverted to arecoline by hydrolysis of the ester group at the 3position to produce arecaidine followed by esterification of thearecaidine with methyl alcohol to give arecoline. For a fullerunderstanding of the nature and objects of the invention, reference maybe had to the following examples which are given. merely as furtherillustrations of the invention. and are not to be construed in alimiting sense:v

Example I A solution of 17.3 gms. (0.1 mol) of l-methyl-3-carbomethoxy-4-piperidinol in 25 cc. of xylene. was added to 18 gms.of anhydrous oxalic acid. suspended in 25 cc. of xylene and the mixture.was heated to reflux with stirring. The hydroxy-- piperidine compoundreacted with the oxalic acid to form an oily material which did notdissolve in the xylene but remained suspended therein. Dehydration tookplace at a steady rate with evolution of water which was collected in aconventional Dean-Stark type trap. The reaction was complete in about 3/2 hours as shown by the amount ofwater collected. After cooling toabout C., the mixture was admixed with 50 cc. of water to dissolve thereaction product and the mixture was then cooled to room temperature.After separating the xylene layer from the mixture, the xylene waswashed twice with 15 cc. portions of water and discarded. The combinedaqueous extracts were then treated :with sufficient; potassium carbonateto neutralize the free oxalic acid andrlibeiate thearecoline from itsoxalic acid salt. About .37 gms. of potassium carbonate were used. Theliberated arecoline was recovered from the aqueous .mixture byextracting the mixture four times with 50 cc. portions of isopropylacetate. After drying the combined isopropyl acetate extracts oversodium sulfate, the solvent was distilled off and then the product wasdistilled in vacuo. There was obtained 13.2 gms. of, a light yellowliquid distilling at 88-90 C. at 9 mm. (yield=85% of theory). Theproduct consisted of a mixture of arecoline (l-methyl 3 carbomethoxy-Atetrahydropyridine), the A isomer thereof and unknown by-products, ofwhich about 90% was the desired arecoline. The latter was readilyisolated as the hydrobromide by treatment with three volumes ofethanolic I-IBr solution containing an equivalent weight of anhydroushydrobromic acid. Arecoline hydrobromide separarated from the ethanolsolution as colorless needles on cooling the solution. A second crop wasobtained on concentrating the filtrate and it was recrystallized fromethanol. A yield of 18.17 gms. or 77.3% of theory of arecolinehydrobromide having a melting point of 172l74 C. was obtained.

Example II The dehydration of l-methyl-B-carbomethoxy- 4-piperidinol wascarried out in the absence of a solvent by admixing and heating 18 gms.of anhydrous oxalic acid with 17.3 gms. of the hydroxypiperidinecompound. This mixture was heated to a temperature of 140 C. andmaintained at.

that temperature for 3 hours under atmospheric pressure. The desiredarecoline was isolated from the reaction mixture in the same manner asin Example'I except, of course, that the present example did not requireseparation of any solvent from the dehydration reaction mixture inasmuchas no solvent was employed in the dehydration step. A yield of arecolinehydrobromide of 14.05 gms. or 59.8% of the theoretical yield wasobtained. The product had a melting point of 172-174 C.

Example III A very excellent yield (69%) of the des1red arecoline(hydrobromide M. P. 172-'-174 C.) was obtained from 1 methyl 3carbomethoxy 4 piperidinol by heating 17.3 gms. of the hydroxypiperidinecompound with 18 gms. of oxalic acid at a temperature of 140 C. for 3hours under vacuum and recovering the product as in Example II.

Example IV By dehydrating 1 methyl 3 carbethoxy 4 piperidinol withoxalic acid in the same manner as 1-methyl-3-carbomethoxy-4-piperidinolwas,v

dehydrated in Example II, very excellent yields of homo-arecoline havinga very high degree of purity are obtained.

Example V Arecoline was prepared by heating a mixture of 17.3 gms. of 1methyl -3- carbomethoxy -4- piperidinol and 18 gms. of anhydrous oxalicacid at 155 C. in vacuo for 1 hours. The arecoline,

which was recovered from the reaction mixture as in Example II, gave ahydrobromide salt having a melting point of 173-174 C.

Example VI The acetate salt of 1-methyl-3-carbomethoxy-4-::

Example VII A dehydration reaction was carried out as in Example IIexcept that the reaction mixture was heated for only 2 hours instead offor 3 hours as in Example II. Although the yield of arecoline wasslightl lower than in Example II, the hydro-.

bromide salt of the product had the same excellent melting point of172-174 C. as the hydrobromide of the product of Example II.

Example VIII The hydrochloride salt ofl-methyl-3-carbomethoxyl-piperidinol was dehydrated with anhydrousoxalic acid-by heating two moles of the acid with one mole of the saltof the piperidinol for 3 hours at 140 C. The arecoline was recovered asin the previous examples.

It is evident from the above examples and detailed description that myprocess provides a far more efficient and satisfactory means for thedehydration of the esters of N-methyl-l-hydroxypiperidine-B-carboxylicacid than has previously been available.

Having described my invention what I claim as new and desire to secureby Letters Patent is:

1. A process for dehydrating an ester of N- methyll-hydroxy piperidine 3carboxylic acid which comprises-heating said ester with anhydrous oxalicacid at a temperature above C.

2. A process for dehydrating an ester of N- methyl- 4-hydroxypiperidine- 3 -carboxylic acid which comprises heating saidester with anhydrous oxalic acid at a temperature between about 100 C.and about 160 C.

3. A process for dehydrating the methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating said esterwith anhydrous oxalic acid and a hydrocarbon solvent having a boilingpoint between about 100 C. and 160 C. said heating being carried outunder reflux conditions. 1

4. A process for dehydrating the methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating said esterwith anhydrous oxalic acid at a temperature of from about- C. to about150 C.

5. A process for dehydrating the methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating said esterwith anhydrous oxalic acid and a hydrocarbon solvent having a boilingpoint between about 130 C. and about 150 C. said heating being carriedout under reflux-conditions.

6. A process for dehydrating the methyl ester of N-methyl- 4-hydroxypiperidine- 3 -carboxylic acid which comprises heating saidester with anhydrous oxalic acid at a temperature of about C. for fromabout two and a half hours to about four hours.

7. A process 'for dehydrating the methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating a mixtureof said ester, anhydrous. oxalic acid and xylene under reflux'conditionsfor from' about two and a half to about four .hours.

.' 8. A processiordehydrating the. methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating said esterwith anhydrous oxalic acid at a temperature of about 140? C. for aboutthree and a half hours.

9. A process for dehydrating the methyl ester of N-methyl -4-hydroxypiperidine -3- carboxylic acid which comprises heating a mixtureof said ester, anhydrous oxalic acid and xylene at the refluxtemperature of the xylene for about three and a half hours.

JOSEPH LEVY.

REFERENCES CITED The following references are of record in the file ofthis patent:

l UNITED STATES PATENTS Number Name Date 2,451,738 Isler Oct. 19, 1948 5FOREIGN PATENTS Number Country Date 66,866 Germany 1891 OTHER REFERENCESDankova: Chem. Abstracts, 1943, p. 381.

Johnson: Acetylenic Compounds, pp. 51,

1. A PROCESS FOR DEHYDRATING AN ESTER OF NMETHYL-4-HYDROXY PIPERIDINE-3- CARBOXYLIC ACID WHICH COMPRISES HEATING SAID ESTER WITH ANHYDROUSOXALIC ACID AT A TEMPERATURE ABOVE 100* C.